For many neurological disorders including Alzheimer Disease (AD), current therapies are largely palliative and based on small molecule designs. However, studies have begun to examine the use of stem cells to both treat and model neurodegenerative disease. Although stem cells have been suggested as a potential therapy for AD, to date this approach has not been directly tested in animal models. Consequently, it is critical to obtain pre-clinical evidence to determine whether neural stem cell (NSC) transplantation can offer symptomatic or disease-modifying effects for AD. In preliminary studies, we have found that short-term transplantation of murine NSCs into aged triple transgenic mice (3xTg-AD) improves cognitive function. Interestingly, NSCs rescue cognition not by differentiating into neurons or altering levels of AB or tau, but rather by increasing levels of brain-derived neurotrophic factor and enhancing endogenous hippocampal synaptic connectivity. These initial findings suggest that NSC transplantation may provide a promising therapeutic approach. However, AD manifests as a long-term and progressive illness. Thus, it is critical to determine whether NSC transplantation can provide benefits across an extended duration. Here we propose to perform a longitudinal examination of the effect of NSC transplantation on AD-related cognitive function in 3xTg-AD mice. We hypothesize that the long-term effectiveness of NSC-based therapies can be improved upon by combining both trophic and disease-modifying approaches. Thus, we will also examine whether NSCs engineered to express an AB-degrading enzyme can provide more substantial long-term benefit. In addition to their potential therapeutic use, stem cells are being actively studied as a novel and powerful approach to model human disease. To begin to examine the use of stem cells to model AD we therefore propose to generate induced pluripotent stem cells (iPSCs) from AD and control patient fibroblasts Comparisons of AB and tau and their various assembly and phosphorylation states will determine whether genetic factors influence the production, oligomerization, or degradation of these proteins. Likewise analysis of the survival of iPSC-derived neurons in response to AB oligomer treatment will be examined to determine whether AD iPSC-derived neurons are innately more susceptible to disease-related insults.